The aim of this study was to evaluate the effect of two models of hypertension on serum ADMA concentrations and whether the changes of serum ADMA concentrations are reversible by removing the cause of hypertension.
Endothelial dysfunction is a major risk factor for cardiovascular disease which is accompanied with reduced nitric oxide (NO) bioavailability [
As an NO synthase inhibitor, ADMA has an important role in vascular homeostasis. There is a correlation between ADMA levels and cardiovascular morbidity and mortality [
The experiments were conducted in 48 male wistar rats, age and weight matched housed in a temperature-controlled animal room with a 12-hour light/dark cycle with free access to rodent chow and tap water. The Ethical Committee of Isfahan University of Medical Sciences approved the study. After one week of habituation to the animal facility, the animals were randomly assigned into four groups: control, deoxycorticosterone acetate salt (DOCA-Salt), sham, and two kidneys one clip (2K1C) (
The animals were randomly divided into hypertensive (
The animals were uninephrectomized via left flank incision. After recovery, hypertensive group received subcutaneously injection of DOCA (30 mg/kg), twice a week and NaCl 1% solution instead of tap water [
Blood samples were taken and centrifuged at 3000 rpm for 20 minutes. Plasma and serums were stored at −70°C for further analysis.
Plasma renin activity (PRA) was measured in 2K1C and sham groups using radioimmunoassay kit (Renctk P2721, DiaSorin Biomedica Diagnostic RIA kit, Italy). PRA was calculated as nanogram angiotensin I generated/mL/h. The PRA assay sensitivity was 0.13 ng/mL.
Serum ADMA concentrations were measured by the competitive ADMA Elisa kit (DLD diagnostika, Germany). The minimum sensitivity of the assay was 0.05
Data are reported as
As illustrated in Table
Systolic, diastolic, and mean arterial pressure (SBP, DBP, and MAP, resp.) in experimental groups. *
Subgroups | SBP (mmHg) | DBP (mmHg) | MAP (mmHg) | |
---|---|---|---|---|
2K1C | Preclipping | 105.65 ± 2.65 | 75.42 ± 3.66 | 82.24 ± 1.31 |
Postclipping | 165.84 ± 3.79* | 102.41 ± 2.59* | 126.72 ± 3.77* | |
Unclipping | 118.40 ± 4.42 | 81.22 ± 3.77 | 86.22 ± 1.91 | |
| ||||
Sham | Preclipping | 104.16 ± 3.96 | 71.33 ± 2.33 | 80.02 ± 1.11 |
Postclipping | 103.72 ± 2.46 | 72.98 ± 5.33 | 81.22 ± 1.35 | |
Unclipping | 112.97 ± 4.56 | 75.34 ± 4.76 | 82.44 ± 1.59 | |
| ||||
DOCA | Before experiment | 93.30 ± 3.29 | 80.04 ± 1.02 | 85.07 ± 0.92 |
DOCA | 151.50 ± 2.18# | 105.90 ± 4.32# | 121.52 ± 2.51# | |
DOCA withdrawal | 94.72 ± 4.6 | 77.68 ± 1.92 | 84.42 ± 1.04 | |
| ||||
Control | Before experiment | 96.51 ± 4.2 | 83.74 ± 2.02 | 86.39 ± 2.44 |
Solvent of DOCA | 97.71 ± 2.39 | 82.34 ± 3.76 | 86.12 ± 1.99 | |
Solvent withdrawal | 98.01 ± 3.66 | 81.83 ± 3.04 | 85.98 ± 2.31 |
PRA levels were measured in 2K1C hypertensive rats. Results showed that PRA level was significantly higher in 2K1C compared to sham group (
Serum ADMA concentrations in DOCA-Salt hypertensive group were higher than control, although it was not statistically significant. Reversal of hypertension did not change serum ADMA concentration. In 2K1C hypertensive group, serum ADMA concentration was significantly elevated compare to sham group (
Changes of serum ADMA concentrations before and after induction of hypertension and after blood pressure reduction in DOCA-Salt (a) and 2K1C (b) hypertensive rats.
In the correlation analysis, there was a weak positive correlation between serum ADMA concentration and systolic blood pressure (
Correlation between serum ADMA concentration and systolic blood pressure (
Epidemiological and clinical studies demonstrated that ADMA can be considered as a strong cardiovascular risk factor and predict future cardiovascular events [
In this study, we found that, in DOCA-Salt hypertensive animals, serum ADMA concentration slightly increased while in 2K1C model, it significantly increased and returned to baseline level after unclipping. In a recent study, it is reported that in patients with metabolic syndrome, ADMA levels did not correlate with blood pressure [
The clinical significance of ADMA has been reviewed [
The reason of high plasma ADMA level during hypertension is unknown. Increased shear stress due to high blood pressure may increase ADMA synthesis [
It was shown that lung is the main source of circulating ADMA. In an in vitro study, incubation of endothelial cells with ang II for 24 h increased PRMT expression and increased ADMA level [
Previous studies indicated that ACE inhibitor drugs such as perindopril or enalapril and AT1 receptor antagonists such as losartan or eprosartan reduced serum ADMA concentration in patients with essential hypertension [
In conclusion, it seems that increased serum ADMA concentration during hypertension is dependent on the type of hypertension, and removing the cause of hypertension could reduce it.
The authors thank the Vice Chancellor of Isfahan University of Medical Sciences for their financial support (Grant no. 287267).